EP3564217B1 - P2x4 receptor antagonist - Google Patents

P2x4 receptor antagonist Download PDF

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Publication number
EP3564217B1
EP3564217B1 EP19181298.1A EP19181298A EP3564217B1 EP 3564217 B1 EP3564217 B1 EP 3564217B1 EP 19181298 A EP19181298 A EP 19181298A EP 3564217 B1 EP3564217 B1 EP 3564217B1
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EP
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Prior art keywords
compound
diazepin
naphtho
pain
phenyl
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EP19181298.1A
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German (de)
English (en)
French (fr)
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EP3564217A1 (en
Inventor
Shogo Sakuma
Kunio Kobayashi
Masatoshi Ushioda
Toshiyasu Imai
Kazuhide Inoue
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Kyushu University NUC
Nippon Chemiphar Co Ltd
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Kyushu University NUC
Nippon Chemiphar Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a diazepine derivative having a P2X4 receptor antagonist activity.
  • the ATP receptors are roughly classified into the P2X family of the ion channel type receptors, and the P2Y family of the G protein coupling type receptors, and seven kinds (P2X 1 to P2X 7 ) and eight kinds (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 to P2Y 14 ) of subtypes have so far been reported for each family.
  • the P2X4 receptor (Genebank No. X87763), a subtype of the P2X family, has been reported to be widely expressed in the central nervous system, (Non-patent documents 1 to 5).
  • neuropathic pain is often caused by injury of a peripheral nerve or the central nerve, and it is caused by, for example, after-trouble of operation, cancer, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia.
  • a substance that inhibits the activity of the P2X4 receptor is expected to be a prophylactic or therapeutic agent for pains of nociceptive pain, inflammatory pain, and neuropathic pain caused by after-trouble of operation, cancers, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia.
  • Patent document 2 reported that a benzofuro-1,4-diazepin-2-one derivative represented by the following general formula (A): (in the formula A, R 1 is a halogen, and R 2 is hydrogen, a halogen, nitro, cyano, C(O)-OR 3 , C(O)-NR 4 R 5 , SO 2 -OR 3 , or SO 2 -NR 4 R 5 , or R 1 is hydrogen, and R 2 is a halogen, nitro, cyano, C(O)-OR 3 , C(O)-NR 4 R 5 , SO 2 -OR 3 , or SO 2 -NR 4 R 5 ) has a P2X4 receptor antagonist activity.
  • A benzofuro-1,4-diazepin-2-one derivative represented by the following general formula (A): (in the formula A, R 1 is a halogen, and R 2 is hydrogen, a halogen, nitro, cyano, C(O)-OR 3 , C
  • paroxetine which is an antidepressant, has a P2X4 receptor antagonist activity (Non-patent document 8).
  • a naphtho[1,2-e][1,4]diazepin-2-one derivative represented by the following formula (B): (in the formula B, R I represents hydrogen, a lower alkyl, a lower alkoxy, ,-and R II represents hydroxy, a lower alkyl, a lower alkoxy, tetrazolyl group , a naphtho[1,2-b][1,4]diazepin-2,4-dione derivative represented by the following general formula (C): (in the formula C, R III represents hydrogen, a lower alkyl, a lower alkoxy, ,-and R IV represents hydrogen, a lower alkyl, a lower alkoxy, tetrazolyl group,), and related compounds thereof have a P2X4 receptor antagonist activity, and filed patent applications therefor (Patent documents 3 to 10).
  • a P2X4 receptor antagonist such as paroxetine and a diazepinedione derivative represented by general formula (IX) pharmacologically acceptable salt thereof can be used as a prophylactic or therapeutic agent for neuropathic pain associated with Guillain-Barre syndrome.
  • R 1 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms
  • R 2 and R 3 independently represent a hydrogen atom, an alkyl group having 1-8 carbon
  • R 4 and R 5 independently represent a hydrogen atom and W represents a 5- or 6-membered heterocyclic ring which contains 1-4 nitrogen atoms as ring-constituting elements and which may have a substituent.
  • paroxetine or a P2X4 receptor antagonist such as a diazepine dione derivative that is represented by general formula (IX) is used as a preventive or therapeutic agent for pain associated with herpes zoster in acute phase.
  • P2X4 receptor antagonist such as a diazepine dione derivative that is represented by general formula (IX)
  • any safe medicament in the form of a preparation for oral administration has not been provided which can be easily taken and has a superior P2X4 receptor antagonist activity.
  • An object of the present invention is to provide a diazepine derivative represented by 2-(Dimethylamino)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]nicotinamide, a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof and having a P2X4 receptor antagonist activity.
  • the present invention thus relates to a compound represented by 2-(Dimethylamino)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]nicotinamide as shown in general formula (I), a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof [Formula (I)] (In the formula, R 1 , R 2 , and type of salt are as mentioned in Table 1) [Table 1] R 1 R 2 Salt H NMe 2 2HCl H NMe 2 2MsOH H NMe 2 -
  • the present invention also relates to a P2X4 receptor antagonist containing a compound represented by the aforementioned general formula (I), a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof, as an active ingredient.
  • the present invention further relates to a prophylactic or therapeutic agent for use in preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain containing a compound represented by the aforementioned general formula (I), a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof, as an active ingredient.
  • a prophylactic or therapeutic agent for use in preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain containing a compound represented by the aforementioned general formula (I), a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof, as an active ingredient.
  • Fig. 1 shows results of measurement of the analgesic activity of the compound of the present invention (Example 28).
  • the invention relates to the following compound (2), a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt thereof:
  • the invention relates to the pharmacologically acceptable salt according to claim 1, wherein it is selected from the following (1) or (3):
  • a further embodiment is a P2X4 receptor antagonist containing the compound according to claim 1, a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt according to claim 1 or 2, or a solvate of any of the foregoing as an active ingredient.
  • the invention relates to a prophylactic or therapeutic agent for use in preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain containing the compound according to claim 1, a tautomer or a stereoisomer of the compound, or a pharmacologically acceptable salt according to claim 1 or 2, or a solvate of any of the foregoing as an active ingredient.
  • Examples of the pharmacologically acceptable salts of the compounds represented by the aforementioned general formula (I) include hydrochlorides, mesylates, and alkali metal salts such as those of sodium, potassium, and lithium.
  • stereoisomers of the compounds of the present invention such as cis- and trans-isomers, optically active substances, and racemates, and all of these substances fall within the scope of the present invention.
  • Ph represents phenyl group
  • R 1 , R 2 and R 3 are hydrogen atoms
  • n is an integer of 1
  • Z is an atomic bond
  • A is a pyridine ring, which have a dimethylamino group as substituent
  • the amino compounds represented by the aforementioned general formula (ii) can be obtained by reacting a bromo compound represented by the aforementioned general formula (i) with benzophenone imine in the presence of a palladium catalyst.
  • the diazepine compounds represented by the aforementioned general formula (iv) can be obtained by reacting an amino compound represented by the aforementioned general formula (ii), and a carboxylic acid represented by general formula (iii) in the presence or absence of a condensing agent in a solvent that does not participate in the reaction.
  • the compounds of the present invention represented by the aforementioned general formula (I) can be prepared by referring to the aforementioned synthesis methods and the examples mentioned later, as well as the aforementioned patent documents, prior art references.
  • the P2X4 receptor antagonist activities of the compounds of the present invention were measured as follows.
  • the ATP receptor (human P2X4) was introduced into the 1321N1 cells, and the cells were used as a stable ATP receptor expression system.
  • the P2X4-expressing 1321N1 cells were seeded on a 96-well plate, cultured under the conditions of 37°C and 5% CO 2 for 24 hours, and used for calcium measurement.
  • Fura-2 AM which is a calcium fluorescent indicator, was dissolved in an extracellular fluid for calcium imaging, and the seeded cells were treated with the solution, and left standing at room temperature for 45 minutes so that Fura-2 AM was incorporated into the cells.
  • a microplate reader Fluostar Optima (BMG Labtech), was used.
  • the light emitted from a xenon lamp was passed through 340 nm and 380 nm filters, respectively, and irradiated on the cells, fluorescences of 510 nm, F 340 and F 380 , emitted from the cells were measured, and change of the ratio F 340 /F 380 was used as an index of change of intracellular calcium level.
  • the measurement was performed by adding ATP to each well at a final concentration of 1 ⁇ M, and observing the ATP-induced Ca 2+ response over time. In the measurement, a treatment with a test substance was performed 15 minutes before the addition of ATP, and the inhibitory activity of the test substance was calculated by comparison of the result with the result obtained in the absence of the test substance.
  • P2X receptor family selectivity of the compound of the present invention (compound described in Example 15) was measured.
  • the compound of the present invention showed high selectivity for the P2X4 receptor as shown in Table 3 (Example 27).
  • analgesic activity of the compound of the present invention was measured by using rat neuropathic pain model (modified Chung model). As a result, it became clear that the compound of the present invention has superior analgesic activity (Example 28, Fig. 1 ).
  • the compounds represented by the aforementioned general formula (I), tautomers or stereoisomers of the compounds, or pharmacologically acceptable salts thereof have a P2X4 receptor antagonist activity, and accordingly, it is considered that they are useful as prophylactic or therapeutic agents for pains of nociceptive pain, inflammatory pain, and neuropathic pain. More specifically, they are useful as prophylactic and therapeutic agents for pains accompanying various cancers, pains accompanying diabetic nerve damage, pains accompanying viral diseases such as herpes, arthrosis deformans.
  • the prophylactic or therapeutic agent of the present invention may be used together with other medicaments if needed, and may be used together with, for example, opioid analgesics (morphine, fentanyl), sodium channel blockers (Novocain, lidocaine), NSAIDs (aspirin, ibuprofen). Further, when it is used for cancerous pain, it may be used together with, for example, anticancer agents such as anticancer chemotherapeutic agents.
  • opioid analgesics morphine, fentanyl
  • sodium channel blockers Novocain, lidocaine
  • NSAIDs aspirin, ibuprofen
  • anticancer agents such as anticancer chemotherapeutic agents.
  • the compounds of the present invention can be administered to a human by an appropriate administration method, such as oral administration or parenteral administration.
  • dosage forms such as tablets, granules, powders, capsules, suspensions, injections, and suppositories can be prepared by the methods usually used in the field of pharmaceutical manufacturing.
  • excipients for manufacturing such preparations, in the case of tablets, for example, usual excipients, disintegrating agents, binders, lubricants, dyes are used.
  • excipient include lactose, D-mannitol, crystalline cellulose, glucose
  • disintegrating agent include starch, carboxymethylcellulose calcium (CMC-Ca)
  • examples of lubricant include magnesium stearate, talc
  • binder include hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP).
  • solvents, stabilizers, dissolving aids, suspending agents, emulsifiers, soothing agents, buffering agents, preservatives are used.
  • the compounds of the present invention as the active ingredient can usually be administered to an adult in a daily dose of 0.01 to 100 mg in the case of injection, or a daily dose of 1 to 2000 mg in the case of oral administration, but the dose may be increased or decreased depending on age, symptoms, .
  • the compounds of the present invention include highly safe compounds such as those not showing the hERG potassium ion channel inhibitory activity, and they are also superior P2X4 receptor antagonists that can be made into easily-taken preparations for oral administration. Therefore, they are useful as prophylactic and therapeutic agents for nociceptive pain, inflammatory pain, and neuropathic pain.
  • the reaction mixture was cooled to room temperature, then water (500 mL) and ethyl acetate (500 mL) were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour.
  • the organic layer was washed with saturated aqueous sodium hydrogencarbonate, and then with saturated brine, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, and the residue was concentrated from ethyl acetate, and then washed with ethyl acetate, and then with hexane to obtain the title compound (54.7 g) as pale yellow crystals.
  • the P2X4 receptor antagonist activities of the compounds of the present invention were measured as follows.
  • the 1321N1 cells stably expressing human P2X4 receptor were seeded on a 96-well plate, cultured under the conditions of 37°C and 5% CO 2 for 24 hours, and then used for intracellular calcium measurement.
  • Fura-2 AM which is a calcium fluorescent indicator, was used for the intracellular calcium measurement.
  • Fura-2 AM dissolved in an assay buffer was added to the cells, the cells were left standing at room temperature for 45 minutes so that Fura-2 AM was incorporated into the cells, and then the plate was used for the fluorescence measurement.
  • the treatment of the cells with each test substance was performed 15 minutes before the addition of ATP, and inflow of calcium into the cells as a response induced by the addition of ATP was measured over time by using a microplate reader.
  • the ratio of fluorescence values obtained with excitation lights of 340 nm and 380 nm was used as an index of the change of intracellular calcium level, and the inhibitory activity of the test substance was calculated on the basis of the comparison with the value obtained in the absence of the test substance (control).
  • Example 15 As shown in Table 3, the compound described in Example 15 showed high selectivity for the P2X4 receptor. Species-specific difference of the P2X4 receptor inhibitory activity was not observed among human, mouse, and rat.
  • the analgesic activity of the compound of the present invention was measured by the following method.
  • Rat neuropathic pain model (modified Chung model) was prepared according to the method of Kim, S.H., Chung, J.M. et al. (An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50, 355-363 (1992 )). More specifically, under isoflurane anesthesia, back hair of rats was extensively shaved, the shaved parts were wiped with rubbing alcohol, the rats were fixed in the prone position on a heating pad, and the skins were cut and opened along the dorsal median line on the upper and lower sides of the sacroiliac bone. The left lateral paravertebral muscle was separated in the sacral region, and then the ligament was separated. The sacroiliae rim and the upper part thereof were cut and opened along the pyramid, the L5 spinal nerve was ligated, and the nerve was cut on the peripheral side. Then, the operative wound was sutured.
  • the pain threshold (paw withdrawal threshold (g)) was measured by stimulating the soles of rats with each of seven von Frey filaments (Stoelting Co., TOUCH-TEST SENSORY EVALUATOR) that gave different stimulation strengths, and determining presence or absence of withdrawal response.
  • the 50% threshold was calculated according to the up down method with reference to the method of Chaplan et al. ( Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw, J. Neurosci. Method, 53:55-63 (1994 )).
  • the compound described in Example 15 was repeatedly orally administered to the rats with a sonde for oral administration in rats for 14 days from the day 9 after the modified Chung operation, and effect thereof on the pain threshold measured in the von Frey filament test was observed.
  • pain threshold of the affected limb was increased by 14 days-repeated oral administration of 30mg/kg of the compounds described in Example 15 twice a day (60mg/kg/day), and significant statistical difference between the vehicle group and the compound administration group was found ( Fig. 1 ).
  • the pain threshold was measured 3 hours after the administration.

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EP19181298.1A 2013-07-12 2014-07-11 P2x4 receptor antagonist Active EP3564217B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2013146212 2013-07-12
PCT/JP2014/068540 WO2015005467A1 (ja) 2013-07-12 2014-07-11 Ｐ２ｘ４受容体拮抗剤
EP14822945.3A EP3020707B1 (en) 2013-07-12 2014-07-11 P2x4 receptor antagonist

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EP3564217B1 true EP3564217B1 (en) 2021-01-27

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US (2) US10150744B2 (ja)
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JP (2) JPWO2015005467A1 (ja)
AU (1) AU2014288115C1 (ja)
CA (1) CA2921200C (ja)
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CN115996911A (zh) 2020-06-30 2023-04-21 拜耳公司 具有p2x4受体拮抗活性的取代的n-苯乙酰胺
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WO2022030428A1 (ja) 2020-08-03 2022-02-10 日本ケミファ株式会社 アレルギー反応に伴う症状の予防若しくは抑制又は治療用の医薬組成物
WO2022049253A1 (en) 2020-09-07 2022-03-10 Bayer Aktiengesellschaft Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators
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AU2014288115B2 (en) 2018-05-10
EP3564217A1 (en) 2019-11-06
JP2018172431A (ja) 2018-11-08
CA2921200A1 (en) 2015-01-15
CA2921200C (en) 2021-07-13
EP3020707A1 (en) 2016-05-18
AU2014288115A1 (en) 2016-03-03
ES2753422T3 (es) 2020-04-08
US10150744B2 (en) 2018-12-11
WO2015005467A1 (ja) 2015-01-15
EP3020707B1 (en) 2019-08-21
AU2014288115C1 (en) 2018-11-15
JPWO2015005467A1 (ja) 2017-03-02
US10472333B2 (en) 2019-11-12
US20180319752A1 (en) 2018-11-08
EP3020707A4 (en) 2016-12-07
JP6600388B2 (ja) 2019-10-30
US20170081294A1 (en) 2017-03-23

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